Insulin-dependent diabetes mellitus (IDDM), or type 1 diabetes (T1D), is caused by T-cell mediated, spontaneous autoimmune destruction of the insulin-producing 2 cells in pancreatic islets. A number of genetic factors contribute to T1D risks. The CTLA4 locus has been implicated in risk for T1D by many genetic studies. There is no report of complete loss of function of CTLA4 in humans. It is not the "all or nothing" CTLA4 signaling, but the subtle quantitative variations of expression associated with genetic polymorphisms, that are attributed to susceptibility to T1D. A number of T1D-risk polymorphisms in the CTLA4 locus have been associated with reduced expression of CTLA4 or its splice variants. However, it remains unclear whether and how CTLA4 splice variants function in etiopathogenesis of T1D and how quantitative reduction of a particular splice variant(s) contributes to the etiological and pathogenic pathways of T1D. To validate the impact of CTLA4 splice variant reduction on susceptibility to T1D, RNAi knockdown mouse models will be established, following a proof-of-principle study. This proposal aims to establish the causative role of CTLA4 splice variant reduction in T1D development, and to uncover novel mechanisms of the quantitative biology of CTLA4 splice variants in T1D pathogenesis. Specifically, 1) novel RNAi transgenic mouse models targeting specific CTLA4 splice variants will be generated to pinpoint the impact of a particular splice variant(s) in T1D pathogenesis;2) In vitro human studies will be used to define the quantitative impact of CTLA4 splice variants on T cells responses and regulations. New technologies will be applied to uncover novel mechanisms by which the quantitative variations of CTLA4 splice variants alter T1D risk. This knowledge will help identify new strategies to bridge a diversity of immune tolerance mechanisms to protect beta cells. PUBLIC HEALTH RELEVANCE: Type 1 diabetes causes significant morbidity and premature mortality. Variations of the CTLA4 gene are associated with a higher risk of developing this disease. An understanding of the functional impact of CTLA4 genetic variations will help find new therapeutic targets for type 1 diabetes.